Alpha lipoic acid (ALA) is a naturally occurring eight-carbon fatty acid that is synthesized by plants and animals, including humans and possesses potent antioxidant, anti-inflammatory and mitochondrial protectant properties. ALA induces weight loss, lowers cholesterol, increases glucose uptake, decreases the expression of inflammatory molecules and improves vascular function. We propose to tap the potentials of ALA derivatives for antihypertensive therapies by developing a novel class of therapeutic molecules derived from ALA. Our preliminary in-vivo and in-vitro studies with the prototype compound, INV 65-05 have been encouraging and provide promise that this approach has merit. Accordingly, we plan to undertake the synthesis and characterizations of ALA based therapeutics and propose three specific aims over one year period. In Specific Aim 1a, we plan to optimize the structures using simulation studies and we will synthesize and characterize small molecules derived from naturally available ALA. In specific aim 1b, we will test ACE inhibitory functionality and establish their efficacy of select compounds using in-vitro assays for antioxidant effects, endothelial protection. In specific aims 2a-c, we will study the in-vivo efficacy of 2 select multifunctional compounds identified in Aim 1 in lowering hypertension using experimental animal models (spontaneously hypertensive rat stroke prone model). We will evaluate the specific effects of these agents in reducing vascular inflammation, endothelial protection, ACE activity in heart and lung, super oxide generation in the aorta. In specific aim 3, we will further modify lead molecules derived from Aim 1 into "nitric oxide" releasing drugs and propose testing their efficacy with regards to NO release as well as the in-vitro assays. Successful completion of this scientific proposal will result in the creation of a novel class of molecules with unique therapeutic effects. A lead candidate will be identified and further tested through a Phase II grant for pharmacokinetics, safety and toxicity. This will then lead to an IND submission to the FDA for execution of Phase I/II clinical trials. PUBLIC HEALTH RELEVANCE: Hypertension affects millions of adult Americans and is a major risk factor for myocardial infarction, stroke, heart failure, and renal failure. . Alpha lipoic acid (ALA) is a naturally occurring eight-carbon fatty acid that is synthesized by plants and animals, including humans and possesses potent antioxidant, anti-inflammatory and mitochondrial protectant properties. ALA induces weight loss, lowers cholesterol, increase glucose uptake, increases glutathione, decreases the expression of inflammatory molecules and improves vascular function. The objective of this proposal is to design, synthesize, and characterize a new class of bio-compatible molecules possessing multi- functional therapeutics and ideal pharmacokinetic properties based on specific modifications of ALA. The proposed derivatives would have ACE inhibitory properties, lowering blood pressure, antioxidant effects and "nitric oxide" releasing functionality and further study their effects with in vitro and in vivo models. The outcomes of this study will help to further advance the commercial development of such molecules.